Agents which block the formation of second messengers that mediate growth factor action may be of value in cancer chemotherapy. Recently the hydrolysis of phosphatidylinositol-bisphosphate (PIP2) to produce diacylglycerol (DAG) and inositol triphosphate (IP3) has been implicated in the action of a number of growth factors including pIatelet derived growth factor and bombesin. We are therefore examining the chemotherapeutic effects of inhibition of this process and attempting to develop inhibitors of number of the enzymes involved in phosphatidylinositol (PI) metabolism. Specific areas of investigation are as follows. A series of inositol analogs and phospholipids incorporating these analogs are under investigation as inhibitors of phospholipase C. The cellular requirements for myo-inositol and the regulation of myo-inositol metabolism are being studied in collaboration with Dr. John Strong of this laboratory. In collaboration with Dr. E. Sausville of Naval Med. Center we are characterizing the mechanisms of transmembrane signalling by the putative autocrine growth factor bombesin in human small cell lung cancer cells (SCLC).